1. Technical Field of the Invention
The present invention relates to a process for the preparation of sucrose-6-ester and, hence, the preparation of the intensive sweetener sucralose.
2. Description of Prior Art
Sucralose, namely 4,1′,6′-trichloro-4,1′,6′-trideoxy galactosucrose or 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl 4-chloro-4-deoxy-α-D-galactopyranoside (formula I), is a intensive sweetener having a sweetness several hundred times that of sucrose. Its use as a sweetener and sweetening compositions containing it are disclosed in British Patent Specification No. 1,543,167.

Sucralose is derived from sucrose by replacing the hydroxyls at the 4-, 1′-, and 6′-positions with chlorine, in which the stereo configuration at the 4 position is reversed. The major problem in the synthesis of sucralose concerns the chlorination of the 4-, 1′- and 6′-positions of a sucrose molecule without chlorination at other positions.
One way of achieving this is to chlorinate a sucrose derivative having the 2-, 3-, 6-, 3′- and 4′-positions blocked, conveniently by esterification, so that only the 4-, 1′- and 6′-positions are available for chlorination. Such a method is also referred to as a “full-protection method”, since all positions not to be chlorinated are protected (see, for example, U.S. Pat. Nos. 4,801,700; 4,783,526 and 4,362,869, which are explicitly incorporated herein by reference in their entirety). However, the full-protection method is complicated and has technical difficulties in selectively protecting the five positions not to be chlorinated.
In addressing the above issue, recently, a “single-protection method” has been recommended and employed in practice, which involves selective chlorination of a sucrose-6-ester (formula II) at the 4-, 1′- and 6′-positions, followed by deacylation to provide sucralose. Examples of such methods can be found, for example, in U.S. Pat. Nos. 4,950,746; 5,023,329 and 5,089,608, EP 0,475,619A; EP 0,776,903A and GB 2,145,080A, which are explicitly incorporated herein by reference in their entirety.

The single-protection method is based on the discovery that hydroxyls at different positions of sucrose differ in reactivity. For example, the chlorinating reactivity of these hydroxyls decreases orderly as 6, 6′>4>1′>others (see P. H. Fairclough, et. al, Carbohydr. Res., 40,285 (1975); L. Hough, et. al., and GB 1,543,167 and GB 1,543,168 (1979)). Therefore, if the most reactive 6-hydroxyl group is protected with an acyl group, a sucrose-6-ester can be readily converted into sucralose by replacing the more reactive hydroxyls at the 4-, 1′- and 6′-positions with chlorine and then recovering the 6-hydroxyl group.
Formation of a sucrose-6-ester is of the most importance to the single-protection method. Philip J. Simpson, in U.S. Pat. No. 4,889,928, discloses a method of preparing a sucrose-6-ester, which comprises reacting sucrose with a trialkyl orthoacrylate to give a sucrose alkyl 4,6-orthoacylate, hydrolyzing the 4,6-orthoacylate and isomerizing the resulting mixture to provide the desired sucrose-6-ester. This method is complicated, difficult to operate, and low in yield. David S, Neiditch et al., in U.S. Pat. No. 5,023,329, disclose an alternative method of preparing a sucrose-6-ester, which comprises reacting sucrose with a di(hydrocarbyl)tin oxide to produce an organotin-sucrose adduct, which can be readily acylated in situ to afford the sucrose-6-ester. This method is highly selective and more efficient, however it also has disadvantages that a di(hydrocarbyl)tin oxide is needed, of which the regeneration is very complicated, and that the tin compound used is hazardous. An enzymatic method is disclosed in GB 2,145,080A for the preparation of a sucrose-6-ester, which is highly selective, high in yield, and may be performed in mild conditions. However, the screening and processing of an enzyme suitable in this method is quite difficult. As a result, no industrial application of the enzymatic method has been reported till now.
A key step in the synthesis of sucralose is the chlorination of sucrose derivatives, of which various processes have been reported. For example, Water A. Szarek, in Advances in Carbohydrate Chemistry & Biochemistry 28, 225-307 (1973), discloses the preparation of halogenated deoxy-sucrose using various chlorinating reagents; Viehe, et. al., in Angew. Chem. Internal. Edit 12 (10), 808-818 (1979), disclose the chlorination of alcohols with a Vilsmeier reagent obtained by reacting DMF with carbonyl chloride; and Eilingsfeld et al., in Angew. Chem. 72(22), 836-845, (1960), disclose the preparation of Vilsmeier reagents by reacting various chlorine-containing agents with tertiary amides. These studies have provided a theoretical base for the preparation of sucralose. Walkup, et al., in U.S. Pat. No. 4,980,463, disclose a method for chloration of sucrose-6-ester, characterized in that a chloroformiminium chloride salt (a Vilsmeier reagent) obtained by reacting DMF with carbonyl chloride is used as the chlorinating reagent, and DMF is also used as the solvent for chlorination. However, carbonyl chloride is highly poisonous, which may bring inevitably problems to industrial applications. In addition, DMF is miscible with water and many conventional organic solvents, which makes it complicated and inefficient to separate desired products from the resulting chlorinated mixture containing substantive inorganic salts and various organic components by extraction with solvents.